American Journal of Medical Genetics Part A

BackgroundSex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. MethodsWe conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE(R) ALL, Embase, and Web of Science. Studies were included if they enrolled [&ge;]10 participants and excluded if they were case reports, reviews, or meta-analyses. We extracted data from 1,474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For U.S.-based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. ResultsSCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the U.S. (23.6%). Reporting rates of race or ethnicity for U.S. papers increased over the 20-year observation period, with an average increase of 1.5% {+/-} 0.4% per year (p = 0.003), peaking in 2024 with 61.4% of U.S.-based papers presenting demographics. When reported, studies consistently overrepresented non-Hispanic White (p<0.001) and college-educated (p<0.001) participants relative to U.S. census benchmarks. ConclusionsThis systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the U.S., where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQoL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the <15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. ObjectivesDetermine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); describe military service metrics of men with SCAs; compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis to matched controls. DesignCross-sectional, case-control SettingUnited States Veterans Administration Healthcare System ParticipantsBiologic males enrolled in the MVP biobank with genomic identification of an additional X or Y chromosome (cases); controls matched 1:5 on sex, age, and genetic ancestry Main Outcome(s) and Measure(s)Prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index (CCI); rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; standardized mortality ratio (SMR) ResultsAn additional X or Y chromosome was present in 145 and 125 per 100,000 males in the MVP, respectively, with the highest prevalence among men with European and East Asian ancestry. At a mean age of 61{+/-}12 years, 74% of male veterans with 47,XXY and >99% with 47,XYY remained undiagnosed. Individuals with 47,XXY (n=862) and 47,XYY (n=747) had similar military service history, all-cause SMR, and age of death compared to matched controls. CCI and healthcare utilization were higher among individuals with SCA, while several measures of HRQoL were lower. Men with a clinical diagnosis of 47,XXY had higher healthcare utilization but lower comorbidity score compared to those undiagnosed. Conclusion and RelevanceOne in 370 males in the MVP cohort have SCA, a prevalence comparable to estimates in the general population. While these men have successfully served in the military, they have higher morbidity and report poorer HRQoL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics. KEY POINTSO_LIComparable to the general population, approximately 1 in 370 male veterans have a sex chromosome aneuploidy, but most are undiagnosed. C_LIO_LIMen with X or Y chromosome aneuploidy successfully complete US miliary duty with similar service history compared to their 46,XY peers. C_LIO_LIMedical comorbidities and healthcare utilization metrics are higher in male veterans with 47,XXY and 47,XYY during aging, however life expectancy is similar to matched controls. C_LI

ObjectiveOrofacial clefts may involve the complete vertical thickness of the lip (complete) or partial thickness (incomplete). This study evaluates side preference for completeness in nonsyndromic asymmetric bilateral and unilateral cleft lip with or without cleft palate (NSCL/P). DesignWe studied 4 multiethnic cohorts from North and South America, Asia, and Africa, including 3,561 individuals with NSCL/P. Associations between cleft completeness, sex, ethnicity, and race were assessed using Chi-square or Fishers exact test (=0.05). ParticipantsPatients with NSCL/P with complete information on cleft type and completeness were included. Our main goal was to analyze side preference of complete clefting in different demographic groups, sex and race. ResultsAmongst asymmetric bilateral cases, left side completeness was significantly more frequent than the right side (73.7% vs. 26.3%; p<0.001). No associations observed for sex or race with ethnicity showing a trend toward significance (50.0% vs. 25.5%; p=0.088). Amongst symmetric bilateral and unilateral cases, Hispanics exhibited completeness more frequently than non-Hispanics (96.4% vs 89.5%; p<0.001; 84.1% vs. 79.7%; p<0.001). For unilateral cases, completeness showed no side preference. Caucasians were less likely to exhibit complete clefts compared to Asians, Blacks, or other racial groups (68.7% vs 84.9% or 81.2% or 81.7%; p<0.001). Females more frequently presented with completeness than males (81.2% vs 76.6%; p=0.003). ConclusionsIn NSCL/P with bilateral asymmetry, the left side is more often complete than the right side. Although unilateral left-sided clefts are more common overall, completeness shows no side preference. Race and ethnicity demonstrate significant associations with cleft severity patterns.

Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of LV size and function were compared between patients with and without dysautonomia, as well as to reported values from healthy controls. Dysautonomia was identified in 71% of female and 56% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 39% to >80%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is highly prevalent in patients with hEDS/HSD, exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Our study of 61 children with Ogden Syndrome, an X-linked disorder due to NAA10 gene mutations, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure-to-thrive diagnostic range; although dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with OS includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in OS probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G-tube or GJ-tube fed probands demonstrates that G/GJ-tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if OS children are not tracking above the FTT range past 1 year of age despite such efforts, they should promptly undergo G-tube placement to avoid prolonged growth failure. If G-tubes are not immediately inducing weight gain after insertion, recommendations include altering formula, increasing caloric input, or exchanging a G-tube for a GJ-tube by means of a minimally invasive procedure. Future directions could include a prospective natural history study investigating whether G/GJ tube insertion affects the cognitive trajectory, rate of reaching developmental milestones, and GI symptomatology of OS children in a positive or negative manner.

BackgroundOutcome measures currently used to assess function in Angelman Syndrome (AS) may be affected by subject anxiety in clinic, a disconnect between the normed age range of the measure and the study population, and a reliance on caregiver report. This study aimed to develop and pilot a novel outcome for AS, the Angelman Syndrome Video Assessment (ASVA) for the assessment of everyday functional skills in individuals with AS in their home environment. MethodsThe task list was informed by published conceptual disease models and determined by a team of experts based on family and clinician input. The study was conducted remotely in the home environment, with families capturing videos of everyday activities and participating in an exit interview about their experience. Videos were evaluated, and caregiver interview transcripts were coded and analyzed to determine whether each task would be included in the finalized measure. ResultsEleven dyads completed the study. The video completion rate was 96%, with 99% of the submitted videos meeting quality standards. Caregivers endorsed the value of assessing people with AS in the home environment. The video capture list was reduced from 27 to 17 tasks. ConclusionsThe ASVA is a novel tool that captures data on the daily functioning of individuals with AS in their home environment. This tool presents a potential new way to evaluate subject function in clinical trials and for clinical care.

Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a parent exhibiting low-level mosaicism. Of the variants, 20 are truncating (frameshift or nonsense), and the remaining five individuals have missense variants (with one of these in three family members). One of the missense variants has been found in at least two other affected individuals. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

ObjectiveWolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. ApproachPatient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants and statistical analysis was performed using unpaired and paired t-tests and one- and two-way ANOVA with Tukeys or Dunnetts tests. ResultsA greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by optic atrophy emerging significantly earlier in patients with 2 nonsense/frameshift alleles compared with 0 missense transmembrane variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy. Summary / ConclusionsThe results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

ObjectivesTo develop within-patient meaningful score differences (MSDs) on the Bayley Scales of Infant Development, Fourth Edition (Bayley-4), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), for individuals with Angelman syndrome (AS). MethodsA Delphi method, involving a panel of 19 caregivers of individuals with AS, was used to establish MSDs for Bayley-4 and Vineland-3 Growth Scale Values. MSD was defined as the smallest change that would noticeably impact the daily functioning of an individual with AS or family quality of life in a way that was important to the individual with AS or their family. For each subscale of the Bayley-4 and Vineland-3, the panel was presented with 2 to 4 vignettes describing varying levels of baseline functioning and asked to select a MSD from a range of potential values. An iterative process involving three rounds of ratings and two rounds of discussion was used to build consensus. The median caregiver rating from round 3 was retained as the final recommended MSD value for each vignette. ResultsFinal MSD ratings for the five subscales of Bayley-4 and 10 subscales of the Vineland-3 had an agreement rate of 70% or higher. MSD thresholds for each subscale were not single cut-offs, but rather reflected a range of MSD values dependent on level of baseline functioning. ConclusionsThe Delphi Panel method incorporates the caregiver perspective to provide preliminary estimates of what constitutes meaningful within person change on the Bayley-4 and Vineland-3 in individuals with AS with various levels of baseline functioning. Highlights To acquire regulatory approval in drug development, sponsors must demonstrate both statistical significance and clinical meaningfulness of a treatment effect.While several clinical trials are underway in AS, within person meaningful score difference thresholds are not yet established for the most commonly used outcome measures, namely the Bayley and Vineland. Aligning with FDA guidance, we have developed an innovative qualitative approach using a Delphi panel to incorporate caregiver perspectives in defining meaningful change and generated preliminary patient-informed meaningful score differences (MSDs) for individuals with Angelman Syndrome. What caregivers of individuals with AS consider to be a MSD on the measures depends primarily on the baseline severity of their childs presentation.

Introduction3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. MethodsDetailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next generation phenotyping platform Face2Gene (FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls, using a proprietary algorithm. Area under the curve of receiver operating characteristic curves (AUC-ROC) were used to determine the capacity of Face2Gene to identify 3q29del cases against controls. ResultsIn this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006). ConclusionThis study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.

PurposeGenome sequencing (GS) is potentially the most suitable diagnostic tools for fetal CNS structural anomalies. However, its efficacy hasnt been proved in large cohort of fetal CNS structural anomalies. MethodsPatients were enrolled by a multiple-level referral system when fetal CNS structure anomalies were found by ultrasonography. Samples from fetuses were subjected to GS. ResultsData of 162 fetuses with 11 frequent types of CNS anomalies was collected. The overall diagnosis yield of GS was 38.9%. 36(20.3%) fetuses were detected with chromosomal anomalies and pathogenic CNVs. Pathogenic or likely pathogenic single-gene variants and intragenic CNVs were found in 24 and three fetuses, contributing 14.8% and 1.9% diagnostic yield respectively. The diagnostic rate in 41 fetuses with CNS malformation combined with anomalies out of brain was as high as 73.3%. Malformations of the posterior cerebral fossa, abnormal neuronal proliferation and migration have the highest diagnostic rates. NTDs had the second lowest diagnostic rates of 14.7% and none pathogenic variants were found in ultrasound anomalies that suggested destructive cerebral lesions. ConclusionGS is an efficient genetic testing tool with the diagnostic power compared to current CMA plus ES procedure in fetal CNS anomalies evaluation.

Background and objectivesSingle gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. MethodsWe analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety/practicality of the intervention, and anticipated intervention efficacy. ResultsWe found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as actionable, defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the primary disease mechanism, 16 had specific prevention strategies, and 26 had specific symptom management recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have clinical utility with 97% of outcomes being moderate-high severity if left untreated and 62% of interventions predicted to be of moderate-high efficacy. Most interventions (71%) were considered moderate-high safety/practicality. DiscussionOur findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety/practicality indicates moderate-high clinical utility of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

ObjectiveTo evaluate symptoms of pediatric feeding disorders in a sample of individuals with 3q29 Deletion Syndrome. Previous research has found that individuals with 3q29 deletion syndrome (3q29Del) may experience elevated feeding concerns in early childhood; however, the specificity of these feeding concerns in this pediatric population is not well understood. MethodsWe compared individuals with 3q29Del (n = 60) to matched controls (n = 59) using an 11-item survey that assessed commonly reported symptoms associated with pediatric feeding disorders. An exploratory analysis also examined individuals with 3q29Del with and without a comorbid autism spectrum disorder (ASD) diagnosis. ResultsCaregivers of 3q29Del cases reported higher incidences of feeding concerns on all 11 items included in the survey. This included statistically significant differences in food refusal behaviors, rejection of one or more food group, and a history of failure to thrive. Parents of children with comorbid autism were more likely to report concerns regarding rejection of one or more food group compared to children with 3q29Del without autism. ConclusionsResults suggest individuals with 3q29Del experience increased symptoms of pediatric feeding disorders. Future research should include a more thorough multidisciplinary evaluation to further document the severity and identify optimal remediation strategies.

ObjectiveAutosomal dominant pathogenic variants in the WFS1 gene can cause a broad spectrum of WFS1-related disorders. These disorders present with a range of phenotypic manifestations, including isolated low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, isolated diabetes mellitus, and early-onset cataracts. In general, WFS1-related disorders represent a milder spectrum of conditions linked to pathogenic WFS1 variants, except for Hattersley-Urano syndrome, which is characterized by early-onset diabetes mellitus, optic nerve atrophy, cataracts, hypotonia, intellectual disability, and developmental delay. By contrast, autosomal recessive WFS1 variants result in Wolfram Syndrome type 1, a rare neurodegenerative disorder characterized by early-onset diabetes mellitus, optic nerve atrophy, arginine vasopressin deficiency, hearing loss, and cerebellar and brainstem atrophy. Although WFS1-related disorders have been increasingly recognized, additional data are needed to understand their clinical progression and long-term outcomes. Our study aims to expand knowledge on the severity and progression of WFS1-related disorders by reviewing clinical data from patients with autosomal dominant pathogenic WFS1 variants. ApproachWe obtained clinical data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. We included participants with autosomal dominant WFS1 pathogenic variants who were diagnosed with optic nerve atrophy and sensorineural hearing loss. Eleven participants with autosomal dominant WFS1 variants meeting these criteria were identified. ResultsThe 11 cases included five distinct autosomal dominant WFS1 variants: c.923C>G (p.Ser308Cys), c.2051C>T (p.Ala684Val), c.2389G>T (p.Asp797Tyr), c.2456A>C (p.Gln819Pro), and c.2590G>A (p.Glu864Lys). Among these, the p.Gln819Pro variant has not been previously reported in the literature. The median age of optic atrophy diagnosis was 10 years (quartiles: 6.0 and 19.0 years). Visual acuity did not significantly differ between the left (OS) and right (OD) eyes (p = 0.8901). The least square best-corrected visual acuity (BCVA) mean for the right eye was 0.2114 {+/-} 0.01903 and for the left eye, 0.2153 {+/-} 0.01903. Age was not significantly related to best eye BCVA (p = 0.9196), with an estimated change of -0.0002 (95% CI [-0.003, 0.003]) per year. Patient age was also not correlated with binocular BCVA (p = 0.5994), with an estimated change of 0.00075 (95% CI [-0.0021, 0.0036]) per year. Mean retinal nerve fiber layer (RNFL) thickness was not significantly related to age (p = 0.1604), with an estimated annual change of 0.1486 (95% CI [-0.659, 0.363]). However, removing an influential outlier resulted in a significant relationship between RNFL thickness and age (p = 0.0160), with an estimated change of 0.2114 (95% CI [0.045, 0.377]) per year. Hearing loss diagnoses occurred at a median age of 2.0 years (quartiles: 1.5 and 2.0 years). All participants used hearing aids (11/11); six (6/11) had cochlear implants, while three (3/11) used external hearing aids. The median time between hearing loss diagnosis and hearing aid use was 4.0 years (quartiles: 2.5 and 8.0 years). ConclusionThis study contributes to the growing understanding of WFS1-related disorders caused by autosomal dominant WFS1 variants. In particular, it highlights two clinical phenotypes of a novel WFS1 variant and provides valuable insights into the progression of optic nerve atrophy and hearing loss management.

Hearing loss is one of the most common sensory disorder and approximately 466 million people have disabling hearing loss worldwide. This study was conducted to identify the mutations in the GJB2, GJB3, and GJB6 genes in an Indian cohort with non-syndromic sensorineural hearing loss and ascertain its use for genetic testing. 31 affected individuals with prelingual bilateral non-syndromic severe to profound sensorineural hearing loss were identified based on clinical evaluation and audiometric assessment. Sanger Sequencing method was used. Six out of 31 affected individuals showed pathogenic nonsense mutations in GJB2 gene, accounting to 19.3%. Of the 6 affected individuals, 5 were homozygous for c.71G>A(p.Trp24Ter) and one was compound heterozygous for c.71G>A and c.370C>T(p.Gln124Ter). Missense mutations [c.380G>A(p.Arg127His) and c.457G>A(p.Val153Ile)], and 3 UTR variations were also identified in GJB2 gene. GJB3 and GJB6 genes showed only silent mutations and 3 UTR variations. 19.3% of affected individuals showing pathogenic mutations in GJB2 gene in our cohort is comparable to other Indian studies (approximately 20%) and it is less as compared to Caucasian, Japanese, and Chinese studies (approximately 50%). Lower occurrence of pathogenic mutations in GJB2 gene in our cohort and other Indian studies as compared to other Caucasian, Japanese and Chinese studies, and absence of pathogenic mutations in GJB3 and GJB6 genes indicates that these genes may have a limited role in the Indian population. Hence there is a need to identify genes that play a major role in the Indian population so that they can be used for genetic testing for NHSL to aid in accurate and early diagnosis.

A wide range of behavioral phenotypes has been described in PWS patients including autism spectrum disorder (ASD). The prevalence of behavioral disorders was studied in 292 participants over 3 years with genetically confirmed PWS (N=164 females and N=128 males) with deletion (N=182) and UPD (N=99). The prevalence of ASD, and other behavioral disorders was tested for association with gender, genetic subtypes, and growth hormone (GH) treatment. The prevalence of ASD in PWS individuals was 19.5%, in concordance with previous studies at 25%. The frequency of ADHD was 10.7%. The mean age at diagnosis for ASD, ADHD, and disruptive behavior was 14.9{+/-}10.5, 9.3{+/-}5.9, and 19.6{+/-}14 years, respectively. There was no statistically significant difference in the prevalence of ASD and ADHD between deletion and UPD subjects, and between GH-treated and non-treated subjects. Patients with deletions had higher frequencies of anxiety than those with UPD(p=0.006). GH-treated participants had a lower frequency of depression and a higher frequency of anxiety than non-treated participants (p=0.04, p=0.02, respectively). This is the largest study to evaluate an association between genetically confirmed PWS and ASD. We found no significant difference in the frequency of ASD and other behavioral disorders across the genetic groups and GH treatment.

LBX1 is a developmental gene involved in skeletal muscle development and somatosensory functioning and proven to be an important gene involved in Adolescent Idiopathic Scoliosis (AIS) etiology. Variant rs11190870 is located 7.5 kb downstream of LBX1 gene and is part of haplotype that is reported to provide risk for AIS. Several studies, including various Genome Wide Association, replication and meta-analyses studies have implicated its association with AIS in different populations. However, any such study is altogether lacking in South-Asian Indian populations. In this first genetic association study for AIS from the region, we tried to replicate association of variant rs11190870 in 95 AIS cases and 282 healthy non-AIS controls from Northwest India. The genotyping was carried out on a Realtime PCR using TaqMan allele discrimination assay and the variant was found to be following Hardy Weinberg equilibrium. The statistical analyses of the genotyping data did not show significant association (p=0.66) of variant rs11190870 with AIS in the population of Northwest India. The results are interesting findings in a population that has never been studied before for AIS susceptibility. However, the findings can be attributed to under power study thus, need evaluation in a large sample set from the population. Interestingly, frequency distribution of the variant in Indian control population datasets was found to be different than other global populations. Linkage Disequilibrium (LD) differences in the genomic region were also observed in these populations while analysing 1000Genomes phase 3 data. It hints at existence of either haplotypic differences in LBX1 locus in South-Asian Indian populations with respect to other populations or genetic heterogeneity in AIS susceptibility. This lays a foundation for genome wide association study (GWAS) in Indian populations cohort, for better understanding of AIS, a task we are pursuing.

Sex chromosome trisomies (SCT) are the most common whole chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed cases, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts--Million Veteran Program, FinnGen, and UK Biobank--to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with SCTs by performing phenome-wide association studies (PheWAS) using electronic health records (EHR) data for each cohort, followed by meta-analysis across cohorts. Association results are presented for each SCT and also stratified by presence or absence of a documented clinical diagnosis for 47,XXY. We identified 2,769 individuals with (47,XXY: 1,319; 47,XYY: 1,108; 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all PheWAS disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency (OR [95% CI] for 47,XXY 4.7 [3.9,5.8]; 47,XYY 5.6 [4.5,7.0]; 4 7,XXX 4.6 [2.7,7.6], venous thromboembolism (47,XXY 4.6 [3.7-5.6]; 47,XYY 4.1 [3.3-5.0]; 47,XXX 8.1 [4.2-15.4]), and glaucoma (47,XXY 2.5 [2.1-2.9]; 47,XYY 2.4 [2.0-2.8]; 47,XXX 2.3 [1.4-3.5]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting one or more X/Y homolog genes may underlie pathophysiology and comorbidities across SCTs.

IntroductionSpinal muscular atrophy (SMA) is a monogenic neuromuscular disorder due to survival motor neuron 1 mutation. Onasemnogene abeparvovec is a US FDA approved single-dose gene therapy for SMA, but is priced at USD 2.1 million per patient which severely limit its accessibility in low-and-middle-income countries (LMIC). We conducted a Phase 1 trial on vesemnogene lantuparvovec, an affordably priced substitute to onasemnogene intended for use in LMICs. MethodsSixteen patients with SMA (eight SMA Type 1 and Type 2 each) received a single dose of intrathecal vesemnogene lantuparvovec. Eleven patients received a low dose (1.5 x 1014 vg) and five received high dose (3.0 x 1014 vg). The primary outcomes were safety, and efficacy with the change from baseline in the developmental gross motor milestones achieved according to World Health Organization (WHO) criteria. ResultsAs of the data cutoff in August 2025, 16 patients enrolled have been followed-up to at least three-month post-treatment. The median ages at diagnosis and dosing were 5 months (0.1, 18) and 12 months (3, 22), respectively. The commonest adverse event (AE) was transiently increased aspartate amino-transaminase which occurred in 11 patients (69%), with one patient having a level twice the upper limit of normal. No patient had required prolonged prednisolone prophylaxis. The most serious AEs were respiratory tract infections which occurred in four (50%) of eight patients with Type 1 SMA, leading to invasive ventilation in 2 and one of them eventually died. Among the eight patients with SMA Type 1, two had gained one WHO milestone at 3-month post-treatment. Among the eight patients with SMA Type 2, at 3-month post treatment, all patients had gained at least one WHO milestone while 2 had gained four milestones and could walk with assistance. ConclusionsIn patients with Type 1 and Type 2 SMA below 24 months, a single intrathecal dose of vesemnogene lantuparvovec was safe and well-tolerated, resulting in improved developmental gross motor milestones which contrast with patients referred to the trial but were untreated. Further studies are necessary to confirm this gene therapys long term safety and efficacy. (ClinicalTrials.gov number NCT06288230.)

BackgroundApproximately 30-40% of genetic and rare disorders manifest with distinct facial patterns. Traditionally, clinical geneticists have qualitatively assessed facial morphology to support preliminary diagnosis and guide confirmatory genetic testing. However, enhancing early diagnostic accuracy through facial biomarkers demands advanced 3D technologies for analyzing facial dysmorphologies, a deeper understanding of condition-specific disruptions in facial development, and a broader inclusion of diverse human populations. To bridge this gap, we analyzed the 3D phenotypes associated with four genetic syndromes in an admixed Latin American population from Colombia. The sample comprised 47 individuals diagnosed with Down (DS), Morquio (MS), Noonan (NS), and Neurofibromatosis type 1 (NF1) syndromes along with 49 controls within the same age range. For each participant, we generated a 3D facial model using a multi-camera photogrammetric system and registered the 3D coordinates of 21 anatomical facial landmarks. Geometric morphometrics methods were employed to characterize syndrome-specific 3D facial dysmorphologies and to assess their variation compared to controls. We also examined whether these syndromes alter the ontogenetic trajectory of facial growth. ResultsFacial shape differed significantly in all syndromes except NF1. Consistently with previous 2D studies, we identified population-specific facial features in Colombian patients that are not reported in individuals of European descent. Pooled 3D analyses revealed a continuous spectrum of facial dysmorphology, with MS displaying the most distinct morphology and an altered ontogenic pattern. Facial size, sex and age were all significant factors modulating facial shape, with diagnosis explaining 14% of variation in facial morphology. ConclusionsOverall, these findings highlight the importance of accounting for interpopulation, sex and ontogenic variation in facial phenotypes to improve the diagnostic utility and of facial biomarkers. Such approaches may contribute to shortening the diagnostic odyssey for individuals with syndromic and rare genetic conditions.